The HIV-infected population in the US is aging and more than half living in the US are 50 years of age or older. Unfortunately, antiretroviral therapy has not restored full health. Anal cancer occurs most frequently among HIV-infected men who have sex with men (MSM) and HIV-infected MSM are at the highest risk of anal HPV-16 infection, the causative agent in 80- 90% of anal cancers , and anal high-grade squamous intraepithelial lesions (HSIL), the precursor to anal cancer. Anal cancer is also a cancer of more advanced age in the general population and men aged 60 years or older are 3 times more likely to be diagnosed with anal cancer compared with men of all ages. Little is known about the relationship between age and HPV infection/HSIL and HIV infection. HIV-infected and uninfected MSM aged 50+ therefore constitute an ideal population in which to address the provocative question PQ4: How do the biology of aging and HIV infection interact in the development of various cancers? The mechanisms by which age contributes to increased risk of cancer are not known. The aging population has evidence for increased inflammation compared with younger people, and these may contribute to persistent HPV infection and reduced clearance of HSIL. Chronic Inflammation is also commonly found in HIV-infected individuals. We propose to conduct a study evaluating the interplay between age group (50-59, 60-69, 70+), HPV and HIV infection. We will perform a cross-sectional study to establish the prevalence of anal HPV/HSIL in these older age groups, and study their association with biomarkers of aging including biomarkers of inflammation. We will then follow men every six months for 3 years who are anal HPV-16 DNA-positive but who have no diagnosis of HSIL evaluating them for persistence of HPV-16 and incident HSIL. We will similarly follow men who are anal HPV-16 DNA-negative and HSIL- negative for incidence and/or reactivation of anal HPV-16 infection. In each prospective cohort we will evaluate the relationship between study outcomes and the biomarkers of the biology of aging. Specific Aims: 1) To determine the age-specific prevalence of anal HPV infection and anal HSIL and their association with biomarkers of inflammation and aging HIV-infected and uninfected MSM aged 50+ years. 2) To determine the persistence of anal HPV-16 infection and incidence of anal HSIL in a cohort of HIV-infected and uninfected MSM aged 50+ years with prevalent anal HPV-16 infection at baseline but no anal HSIL, and their relationship to biomarkers of inflammation and aging. 3) To determine the incidence of newly detectable anal HPV-16 infection and anal HSIL in a cohort of HIV-infected and uninfected MSM aged 50+ years without anal HPV 16 infection and HSIL at baseline, and their relationship to biomarkers of inflammation and aging. This study will provide the first data on HPV infection/HSIL among older HIV-infected individuals on effective ART and determine the role of the biology of aging in the pathogenesis of anal cancer in this population. The results wil inform our understanding of the pathogenesis of anal cancer in both HIV-infected and uninfected populations.